Process of reducing 3-enol sapogenin acylates with sodium borohydride



United States PROCESS OF REDUCING 3-ENOL SAPOGENIN ACYLATES WITH SODIUM BOROHYDRIDE No Drawing. Application March 20, 1952 Serial No. 277,715

Claims priority, application Mexico August 2, 1951 7 Claims. (Cl. 260-23955) The present invention relates to a method for the production of cyclopentanophenanthrene compounds.

More particularly the present invention relates to a new method for the reduction of enol sapogenin acylates, i. e. A or A -3-ol esters to the corresponding A or A compounds. The process of the present invention provides an economical method for the production of A and A compounds which are valuable intermediates in the introduction of ll-oxy groups in the steroid molecule. Asis well known, ll-oxy groupings are at the present time believed to be an essential characteristic of valuable therapeutics such as cortisone and compound F.

In United States application Serial No. 219,531, now abandoned, filed April 5, 1951, there isdisclosed a method for the production of certain A353? and A com- .pounds which may be characterized by the following formulas:

wherein R may be 'an esterification residue of a lower fatty acid such as acetic or propionic and Y may be either of the following groups characteristic of the sapo- In accordance with the present invention it has now been discovered that compounds of the aforementioned type can be readily reduced with sodium borohydride to the corresponding A or A compounds in good atent together with a small quantity of water.

a lC

yield and without effecting the side chain as exemplified by the following equations:

In the above equations R and Y indicate the same radicals 'asheretofore mentioned and K may be hydrogen or the esterification residue of a lower fatty acid such as acetic or propionic.

In practicing the process of the present invention the starting compounds such as, for example, 3acetoxyspir'ostatetraene are dissolved in a suitable organic solvent such as a lower alcohol, for example, ethyl alcohol, or mixtures of dioxane and a lower alcohol, i. e. ethyl or methyl alcohol. The sodium borohydride may then be added'thereto. Prior to adding the sodium 'borohydride to the solution of the starting compounds, the sodium borohydride may be dissolved in a suitable solvent, as for example, a lower alcohol solvent, such as methanol, The reaction may be carried out by allowing the solution containing the sodium borohydride and the starting compound to remain at room temperature for a=relatively long period of time, as for example, forty-eight hours. Thereafter the solution may be concentrated in vacuum, taken up in a suitable solvent, suchas ether, and washed with, for example, a dilute sodium hydroxide solution and water, dried and evaporated to dryness. .A crystalline residue consisting of, in the case of the 3-acetoxy A -22- isospirostatriene, of A -22-isospirostadiene-3fi-ol, is produced. This residue may ,be furtherpurified, as by recrystallization, from a suitable solvent, such as ethyl acetate, to give the pure compound; or, in the alternative, the crystalline residue maybe directly acetylated without further purification, as for example, with pyridine and acetic anhydride to form the corresponding acetate. Instead of using room temperature for the reaction, higher temperatures may be utilized, as for example, the refluxed temperature of the solvent used, i. e. temperatures of the order of C. These higher temperatures are especially desirable in the case of the tetraene compound previously mentioned. In the case of the triene compound lower temperatures than room temperatures may be desirably used. Thus, the solution of ,3-acetoxy A -22-isospirostatriene may be cooled with ice and added in an ice-cold condition to a solution. of sodium borohydride. Thereafter the reaction may occur by .allowing the reaction solution to stand at 10 C. for approximately one day and completed by heating the mixture on a steam bath for a short period, as for example thirty minutes. Insead of the direct acetylation of the crystalline material or product, the product, as previously set forth, may be purified and the crystalline mother liquors-may be then directly acetylated in order to produce .a further yield of a lower fatty acid ester,

max.

Example I 0,5 "g, of sodium borohydride were added at room temperature to a solution of 1.5 g. of A -22-isospirosta triene-3-ol acetate (melting point 191193 C.) in 500 cc. of ethanol. After leaving the solution 48 hours at roomtemperature, it was concentrated in vacuum, taken up in ether and washed with dilute sodium hydroxide solution and water, dried over sodium sulphate and evaporated to dryness. The crystalline residue was directly acetylated with pyridine-acetic anhydride to yield A -22-isospirostadiene-BB-ol acetate, which, after "cr stallization from benzene-alcohol had a melting point of 201 205 C. and showed ultravioletv absorption maxima at 270,280 and 292 mu.

Example II Example III An ice cold mixture of 1.0 g. of 3-acetoxy-A '-22- isospirostatriene in 40 cc. of dioxane and 60 cc. of

methanol was added in one portion to a solution of 1.6

g. of'sodium borohydride in 40 cc. of methanol and 33 cc. of water. After standing at 10.for 16 hours, the

mixture was warmed for 30 minutes on the steambath,

diluted with water and the solid was collected; yield,

max.

270, 282 and 292 mu, log E 4.07, 4.09, 8.86

Two recrystallizations from ethyl acetate furnished 0.55 g. (60%) of A -22-isospirostadien-3,8-ol with a melting point of 187l90 C. (u) 177 A 270, 280 and 292 mu, log E 4.17, 4.19, 3.99

infrared spectrum identical specimen.

Acetylation of the crystalline mother liquors afforded an additional 10-13% of A -22-isospirostadien-3fi-ol acetate with a melting point of 201-203 C.

the identity of which was confirmed by comparison of its infrared spectrum with that of an authentic sample.

On carrying out the reaction as above but refluxing for 2 hours, the crude product (85% yield) exhibited a melting point of 160-170 C., (a) 99 242, 270, 280 and 292 mu, log E 3.52, 3.87, 3.89,

xEtOH Example IV One gram of 3 acetoxy 35-19(11) 22 isospirostatetraene upon treatment with sodium borohydride as described in Example III (10) produced 0.635 g. (69%) of A -22-isospirostatriene-3B-ol with a melting point of 187-190" C., (u) +121 A23 324 mu, log E 4.14 and inflections at 312 mu (log E 4.10) and 338 mu (log E 4.00).

The acetate prepared by conventional acetylation with that of an authentic 1' it was possible to work in more concentrated solution. Thus, when 0.8 g. of 3-acetoxy-A -22-isospirostatetraene was refluxed for two hours with 1.6 g. of sodium borohydride in 30 cc. each of dioxane and ethanol containing 3 cc. of water, precipitation with water afforded 0.71 g. (97%) of crude A -trien-3p-ol with a melting point of 173-178 C., (u) +113 P 324 mu, log E 4.11

One. recrystallization from methanol led to 0.5 g. (68%) of the pure trienol.

We claim: 1. A process for the production of compounds selected from the group consisting respectively of A spirostadiene-3B-ol and A 9-spirostatrienee3fl-ol having the following formula: H

wherein Y is selected from the cals of the following formula:

group consisting of radiwhich comprises reducing the corresponding lower fatty acid esters of a compound selected from a group consisting respectively of A -spirostatriene-313-01 and A spirostatetraene-3/3-ol with sodium borohydride.

2. A process for the production of compounds selected from the group consisting respectively of lower fatty acid esters of A -spirostadiene-35-o1 and lower fatty acid esters of A -spirostatriene-3fi-ol having the following formula:

m a th wherein R p e n 21 fa y aci acyl group and and wherein Y is selected from the group consisting of radicals of the following formula:

t pw

and

Yipes which comprises reducing the corresponding lower fatty acid ester of a compound selected from the group consisting respectively of A -spirostatriene-3fi-ol and A -spirostatetraene-3,8-ol with sodium borohydride and thereafter acylating.

3. A process for the production of compounds selected from the group consisting respectively of A 22-isospirostadiene-313-ol and A -22-isospirostatriene-Elfi-ol having the following formula:

U ROQ o W3- l Row wherein R represents a lower fatty acyl group which comprises reducing the corresponding lower fatty acid esters of a compound selected from the group consisting respectively of A 22 isospirostatriene 3p 01 and A -spirostatetraene-3fl-ol with sodium borohydride and thereafter acylating.

5. A process for the production of A -22-isospir0stadiene-3fl-ol having the formula:

which comprises reducing 3-acetoxy-A -22-isospirostatriene with sodium borohydride.

6. A process for the production of A 42450- spirostatriene-3fl-ol having the following formula:

which comprises reducing 3-acetoxy-A -22-isospirostatetraene with sodium borohydride.

7. A process for the production of A -22-isospirostatriene-3B-ol having the following formula:

Repair which comprises dissolving a lower fatty acid ester of A -22-isospirostatetraene in a lower alcohol solvent and refluxing with sodium borohydride.

and

No references cited.

UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,860,133 November 11, 1958 George Rosenkmnz et e1.

X1; is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should reegL as corrected below.

Column 1, lines 32 to 50, the formulas should appear as shown below instead. of as in the patenb New column 2, lines 2 to 22, the formula should appear as shown below instead of as in 5 pe ee w Signed and sealed this 24th day of February 1959.

[sea] Attest:

KARL AXLINE, ROBERT (J. WATSON. Attestz'nfiOfl'i'cer. i fl'q wniiisibmr of Patmz e 

1. A PROCESS FOR THE PRODUCTION OF COMPOUNDS SELECTED FROM THE GROUP CONSISTING RESPECTIVELY OF $5,7SPIROSTADIENE-3B-OL AND $5,7,9(11)-SPIROSTATRIENE-3B-OL HAVING THE FOLLOWING FORMULA: 